Intermittent fasting induces rapid hepatocyte proliferation

Nutrient availability fluctuates in most natural populations, forcing organisms to undergo periods of fasting and re-feeding. It is unknown how dietary change influences cell proliferation in the liver. Here, we show that intermittent fasting (IF) promotes rapid hepatocyte proliferation. Mechanistically, IF elicits intestinal production of endocrine FGF15, which activates the {beta}-KLOTHO receptor on hepatocytes to induce proliferation. Furthermore, IF-induced proliferation is locally controlled in hepatocytes by WNT signaling and the WNT target gene Tbx3. IF induces hepatocyte proliferation to re-establish a constant liver-to-body-mass ratio during periods of fasting and re-feeding and maintain the hepatostat. This study provides the first example of dietary influence on adult hepatocyte proliferation and identifies both systemic FGF and local WNT as regulators of this process.